Partial and full agonists of A1 adenosine receptors

ABSTRACT

Disclosed are novel compounds that are partial and full A 1  adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, and myocardial infarction.

FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds that are partialor full A₁ adenosine receptor agonists, and to their use in treatingmammals for various disease states, including modifying cardiacactivity, in particular treatment of arrhythmia. The compounds are alsouseful for treating CNS disorders, diabetic disorders, obesity, andmodifying adipocyte function. The invention also relates to methods fortheir preparation, and to pharmaceutical compositions containing suchcompounds.

BACKGROUND

[0002] Adenosine is a naturally occurring nucleoside, which exerts itsbiological effects by interacting with a family of adenosine receptorsknown as A₁, A_(2a), A_(2b), and A₃, all of which modulate importantphysiological processes. For example, A_(2A) adenosine receptorsmodulate coronary vasodilation, A_(2B) receptors have been implicated inmast cell activation, asthma, vasodilation, regulation of cell growth,intestinal function, and modulation of neurosecretion (See AdenosineA_(2B) Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistovet al., Trends Pharmacol Sci 19:148-153), and A₃ adenosine receptorsmodulate cell proliferation processes.

[0003] The A₁ adenosine receptor mediates two distinct physiologicalresponses. Inhibition of the cardiostimulatory effects of catecholamineis mediated via the inhibition of adenylate cyclase, whereas the directeffects to slow the heart rate (HR) and to prolong impulse propagationthrough the AV node are due in great part to activation of I_(KAdo). (B.Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 andJ. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997)P 2-10). Stimulation of the A₁ adenosine receptor shortens the durationand decreases the amplitude of the action potential of AV nodal cells,and hence prolongs the refractory period of the AV nodal cell. Thus,stimulation of A₁ receptors provides a method of treatingsupraventricular tachycardias, including termination of nodal re-entranttachycardias, and control of ventricular rate during atrial fibrillationand flutter.

[0004] Accordingly, A₁ adenosine agonists are useful in the treatment ofacute and chronic disorders of heart rhythm, especially those diseasescharacterized by rapid heart rate, in which the rate is driven byabnormalities in the sinoatrial, atria, and AV nodal tissues. Suchdisorders include, but are not limited to, atrial fibrillation,supraventricular tachycardia and atrial flutter. Exposure to A₁ agonistscauses a reduction in the heart rate and a regularization of theabnormal rhythm, thereby improving cardiovascular function.

[0005] A₁ agonists, through their ability to inhibit the effects ofcatecholamines, decrease cellular cAMP, and thus have beneficial effectsin the failing heart where increased sympathetic tone increases cellularcAMP levels. The latter condition has been shown to be associated withincreased likelihood of ventricular arrhythmias and sudden death. See,for example, B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991),P 1499-1509 and J. C. Shryock and L. Belardinelli, Am. J. Cardiology,Vol. 79 (1997) P 2-10.

[0006] A₁ agonists, as a result of their inhibitory action on cyclic AMPgeneration, have antilipolytic effects in adipocytes that leads to adecreased release of nonesterified fatty acids (NEFA) (E. A. van Schaicket al J. Pharmacokinetics and Biopharnaceutics, Vol. 25 (1997) p 673-694and P. Strong Clinical Science Vol. 84 (1993) p. 663-669).Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by aninsulin resistance that results in hyperglycemia. Factors contributingto the observed hyperglycemia are a lack of normal glucose uptake andactivation of skeletal muscle glycogen synthase (GS). Elevated levels ofNEFA have been shown to inhibit insulin-stimulated glucose uptake andglycogen synthesis ( D. Thiebaud et al Metab. Clin. Exp. Vol. 31 (1982)p 1128-1136 and G. Boden et al J. Clin. Invest. Vol. 93 (1994) p2438-2446). The hypothesis of a glucose fatty acid cycle was proposed byP. J. Randle as early as 1963 (P. J. Randle et al Lancet (1963) p.785-789). A tenet of this hypothesis would be that limiting the supplyof fatty acids to the peripheral tissues should promote carbohydrateutilization (P. Strong et al Clinical Science Vol. 84 (1993) p.663-669).

[0007] The benefit of an A₁ agonist in central nervous disorders hasbeen reviewed (L. J. S. Knutsen and T. F. Murray in PurinergicApproaches in Experimental Therapeutics, Eds. K. A. Jacobson and M. F.Jarvis (1997) Wiley-Liss, N. Y., P 423-470). Briefly, based onexperimental models of epilepsy, a mixed A_(2A): A₁ agonist, metrifudil,has been shown to be a potent anticonvulsant against seizures induced bythe inverse benzodiazepine agonist methyl6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM, H. KlitgaardEur. J. Pharmacol. (1993) Vol. 224 p. 221-228). In other studies usingCGS 21680, an A_(2A) agonist, it was concluded that the anticonvulsantactivity was attributed to activation of the A₁ receptor (G. Zhang etal. Eur. J. Pharmacol. Vol. 255 (1994) p. 239-²⁴3). Furthermore, A₁adenosine selective agonists have been shown to have anticonvulsantactivity in the DMCM model (L. J. S. Knutsen In Adenosine and AdenneNucleotides: From Molecular Biology to Integrative Physiology; eds. L.Belardinelli and A. Pelleg, Kluwer: Boston, 1995, pp 479-487). A secondarea where an A₁ adenosine agonist has a benefit is in animal models offorebrain ishemia as demonstrated by Knutsen et al (J. Med. Chem. Vol.42 (1999) p. 3463-3477). The benefit in neuroprotection is believed tobe in part due to the inhibition of the release of excitatory aminoacids (ibid).

[0008] Adenosine itself has proven effective in treating disease statesrelated to the A₁ adenosine receptor, for example in terminatingparoxysmal supraventricular tachycardia. However. these effects areshort-lived because adenosine's half-life is less than 10 sec.Additionally, as adenosine acts indiscriminately on the A_(2A), A_(2B),and the A₃ adenosine receptor subtypes, it also provides direct effectson sympathetic tone, coronary vasodilatation, systemic vasodilatationand mast cell degranulation.

[0009] Accordingly, it is an object of this invention to providecompounds that are potent full A₁ adenosine receptor agonists or partialA₁ receptor agonists with a half life greater than that of adenosine,and that are selective for the A₁ adenosine receptor, which will ensurethat undesired side effects related to stimulation or antagonism of theother adenosine receptors are avoided.

SUMMARY OF THE INVENTION

[0010] It is an object of this invention to provide compounds that areselective, partial or full A₁ receptor agonists. Accordingly, in a firstaspect, the invention relates to compounds of Formula I:

[0011] wherein:

[0012] R is hydrogen or lower alkyl;

[0013] R¹ is optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; or

[0014] R and YR¹ when taken together with the nitrogen atom to whichthey are attached represents optionally substituted heterocyclyl;

[0015] R² is hydrogen, halo, trifluoromethyl, acyl, or cyano;

[0016] R³ is optionally substituted cycloalkyl, optionally substitutedaryl; optionally substituted heteroaryl, or optionally substitutedheterocyclyl,

[0017] R⁴ and R⁵ are independently hydrogen or acyl; and

[0018] X and Y are independently a covalent bond or optionallysubstituted alkylene; with the proviso that when R¹ is methyl and Y is acovalent bond, R³ cannot be phenyl when X is methylene or ethylene.

[0019] A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I and at least one pharmaceutically acceptableexcipient.

[0020] A third aspect of this invention relates to a method of using thecompounds of Formula I in the treatment of a disease or condition in amammal that can be usefully treated with a partial or full selective A₁receptor agonist. Such diseases include atrial fibrillation,supraventricular tachycardia and atrial flutter, congestive heartfailure, antilipolytic effects in adipocytes, epilepsy, stroke,diabetes, obesity, ischemia, including stable angina, unstable angina,cardiac transplant, and myocardial infarction.

[0021] Of the compounds of Formula I, one preferred class includes thosein which R³ is optionally substituted aryl or optionally substitutedheteroaryl, especially where R, R², R⁴ and R⁵ are all hydrogen.

[0022] Of these compounds, one preferred group includes compounds inwhich R³ is optionally substituted aryl, especially those in which R³ isoptionally substituted phenyl, R¹ is optionally substituted cycloalkyl,and X is a covalent bond. A preferred subgroup includes those compoundsin which R³ is phenyl substituted by halo, especially fluoro, and R¹ isoptionally substituted cyclopentyl, especially 2-hydroxycyclopentyl.

[0023] A second preferred subgroup includes compounds in which R¹ and R³are both optionally substituted phenyl, X is a covalent bond, and Y isoptionally substituted lower alkylene, especially those compounds inwhich Y is ethylene, propylene or propylene substituted by phenyl.

[0024] A third preferred subgroup includes compounds in which R¹ isoptionally substituted alkyl or optionally substituted phenyl, R³ isoptionally substituted phenyl, and X and Y are both covalent bonds. Apreferred subgroup includes those compounds in which R¹ is lower alkylor 2-fluorophenyl and R³ is phenyl or 2-fluorophenyl.

[0025] Another preferred group includes compounds in which R³ isoptionally substituted heteroaryl, especially those in which R³ isoptionally substituted 1,3-thiazol-2-yl or optionally substituted1,3-benzoxazol-2-yl. A preferred subgroup includes those compounds inwhich R¹ is optionally substituted cycloalkyl or optionally substitutedphenyl, X is a covalent bond, and Y is a covalent bond or alkylene. Amore preferred subgroup includes those compounds in which R¹ isbicycloalkyl, particularly bicyclo[2.2.]hepty-2-yl, and Y is a covalentbond, or R¹ is monocyclic, especially cyclopropyl, and Y is methylene.Another preferred subgroup includes those compounds in which R¹ isphenyl and Y is lower alkylene.

[0026] A second preferred class includes those compounds in which R², R⁴and R⁵ are all hydrogen, and R and YR¹ when taken together with thenitrogen to which they are attached represent a nitrogen containingheterocyclyl. A preferred group includes those compounds in which R³ isoptionally substituted phenyl or optionally substituted heteroaryl and Xis a covalent bond, especially where R and YR¹ when taken together withthe nitrogen to which they are attached represents pyrrolidin-1-yl.

Definitions and General Parameters

[0027] As used in the present specification, the following words andphrases are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

[0028] The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

[0029] The term “substituted alkyl” refers to:

[0030] 1) an alkyl group as defined above, having from 1 to 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0031] 2) an alkyl group as defined above that is interrupted by 1-5atoms or groups independently chosen from oxygen, sulfur and —NR_(a)—,where R_(a) is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, in which Ris alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0032] 3) an alkyl group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1-5 atoms orgroups as defined above.

[0033] The term “lower alkyl” refers to a monoradical branched orunbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms.This term is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

[0034] The term “substituted lower alkyl” refers to lower alkyl asdefined above having 1 to 5 substituents, preferably 1 to 3substituents, as defined for substituted alkyl, or a lower alkyl groupas defined above that is interrupted by 1-5 atoms as defined forsubstituted alkyl, or a lower alkyl group as defined above that has bothfrom 1 to 5 substituents as defined above and is also interrupted by 1-5atoms as defined above.

[0035] The term “alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1 to 20carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbonatoms. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—) and the like.

[0036] The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms.

[0037] The term“substituted alkylene” refers to:

[0038] (1) an alkylene group as defined above having from 1 to 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0039] (2) an alkylene group as defined above that is interrupted by 1-5atoms or groups independently chosen from oxygen, sulfur and NR_(a)—,where R_(a) is chosen from hydrogen, optionally substituted alkyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groupsselected from carbonyl, carboxyester, carboxyamide and sulfonyl; or

[0040] (3) an alkylene group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1-20 atoms asdefined above. Examples of substituted alkylenes are chloromethylene(—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—), methylaminoethylene(—CH(NHMe)CH₂—), 2-carboxypropylene isomers(—CH₂CH(CO₂H)CH₂—),ethoxyethyl (—CH₂CH₂O—CH₂CH₂—), ethylmethylaminoethyl(—CH₂CH₂N(CH₃)CH₂CH₂—), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane(—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—2 OCH₂CH₂—), and the like.

[0041] The term “aralkyl: refers to an aryl group covalently linked toan alkylene group, where aryl and alkylene are defined herein.“Optionally substituted aralkyl” refers to an optionally substitutedaryl group covalently linked to an optionally substituted alkylenegroup. Such aralkyl groups are exemplified by benzyl,3-(4-methoxyphenyl)propyl, and the like.

[0042] The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y—Z, in which Y is optionally substituted alkylene and Z is; optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups are alkyl-O—and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

[0043] The term “alkylthio” refers to the group R—S—, where R is asdefined for alkoxy.

[0044] The term “alkenyl” refers to a monoradical of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 20carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond(vinyl). Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂),1-propylene or allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

[0045] The term “lower alkenyl” refers to alkenyl as defined abovehaving from 2 to 6 carbon atoms.

[0046] The term “substituted alkenyl” refers to an alkenyl group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0047] The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or propynyl, —C≡CCH₃), and the like. In the eventthat alkynyl is attached to nitrogen, the triple bond cannot be alpha tothe nitrogen.

[0048] The term “substituted alkynyl” refers to an alkynyl group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0049] The term “aminocarbonyl” refers to the group —C(O)NRR where eachR is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl orwhere both R groups are joined to form a heterocyclic group (e.g.,morpholino). All substituents may be optionally further substituted byalkyl, alkoxy, halogen, CF₃, amino, substituted amino, cyano, or—S(O)_(n)R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0050] The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, in which Ris alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0051] The term “acyloxy” refers to the groups —O(O)C-alkyl,—O(O)C-cycloalkyl, —O(O)C-aryl, —O(O)C-heteroaryl, and—O(O)C-heterocyclyl. All substituents may be optionally furthersubstituted by alkyl, alkoxy, halogen, CF₃, amino, substituted amino,cyano, or —S(O)_(n)R, in which R is alkyl, aryl, or heteroaryl and n is0, 1 or 2.

[0052] The term “aryl” refers to an aromatic carbocyclic group of 6 to20 carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

[0053] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with from 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0054] The term “aryloxy” refers to the group aryl-O— wherein the arylgroup is as defined above, and includes optionally substituted arylgroups as also defined above. The term “arylthio” refers to the groupR—S—, where R is as defined for aryl.

[0055] The term “amino” refers to the group —NH₂.

[0056] The term “substituted amino” refers to the group —NRR where eachR is independently selected from the group consisting of hydrogen,alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl,heteroaryl and heterocyclyl provided that both R groups are nothydrogen, or a group —Y—Z, in which Y is optionally substituted alkyleneand Z is alkenyl, cycloalkenyl, or alkynyl,. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0057] The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0058] The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to20 carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, andbicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example indan, and the like.

[0059] The term “substituted cycloalkyl” refers to cycloalkyl groupshaving from 1 to 5 substituents, and preferably 1 to 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0060] The term “halogen” or “halo” refers to fluoro, bromo, chloro, andiodo.

[0061] The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

[0062] The term “heteroaryl” refers to an aromatic group (i.e.,unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatomsselected from oxygen, nitrogen and sulfur within at least one ring.

[0063] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl, benzothiazole, or benzothienyl). Examples of nitrogenheterocycles and heteroaryls include, but are not limited to, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,indolizine, isoindole, indole, indazole, purine, quinolizine,isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, phenanthroline, isothiazole, phenazine, isoxazole,phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like aswell as N-alkoxy-nitrogen containing heteroaryl compounds.

[0064] The term “heteroaryloxy” refers to the group heteroaryl-O—.

[0065] The term “heterocyclyl” refers to a monoradical saturated orpartially unsaturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

[0066] The compounds of Formula I include the definition that “R and YR¹when taken together with the nitrogen atom to which they are attachedrepresents optionally substituted heterocyclyl”. Such a definitionincludes heterocycles with only nitrogen in the ring, for examplepyrrolidines and piperidines, and also includes heterocycles that havemore than one heteroatom in the ring, for example piperazines,morpholines, and the like.

[0067] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 5, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a singlering or multiple condensed rings. Preferred heterocyclics includetetrahydrofuranyl, morpholino, piperidinyl, and the like.

[0068] The term “thiol” refers to the group —SH.

[0069] The term “substituted alkylthio” refers to the group—S-substituted alkyl.

[0070] The term “heteroarylthiol” refers to the group —S-heteroarylwherein the heteroaryl group is as defined above including optionallysubstituted heteroaryl groups as also defined above.

[0071] The term “sulfoxide” refers to a group —S(O)R, in which R isalkyl, aryl, or heteroaryl. “Substituted sulfoxide” refers to a group—S(O)R, in which R is substituted alkyl, substituted aryl, orsubstituted heteroaryl, as defined herein.

[0072] The term “sulfone” refers to a group —S(O)₂R, in which R isalkyl, aryl, or heteroaryl. “Substituted sulfone” refers to a group—S(O)₂R, in which R is substituted alkyl, substituted aryl, orsubstituted heteroaryl, as defined herein.

[0073] The term “keto” refers to a group —C(O)—. The term “thiocarbonyl”refers to a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

[0074] “Optional” or “optionally” means that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not.

[0075] The term “compound of Formula I” is intended to encompass thecompounds of the invention as disclosed, and the pharmaceuticallyacceptable salts, pharmaceutically acceptable esters, and prodrugs ofsuch compounds.

[0076] The term “therapeutically effective amount” refers to that amountof a compound of Formula I that is sufficient to effect treatment, asdefined below, when administered to a mammal in need of such treatment.The therapeutically effective amount will vary depending upon thesubject and disease condition being treated, the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

[0077] The term “treatment” or “treating” means any treatment of adisease in a mammal, including:

[0078] (i) preventing the disease, that is, causing the clinicalsymptoms of the disease not to develop;

[0079] (ii) inhibiting the disease, that is, arresting the developmentof clinical symptoms; and/or

[0080] (iii) relieving the disease, that is, causing the regression ofclinical symptoms.

[0081] In many cases, the compounds of this invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

[0082] Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

[0083] Pharmaceutically acceptable acid addition salts may be preparedfrom inorganic and organic acids. Salts derived from inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

[0084] As used herein, “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

[0085] A compound that is an agonist with high intrinsic efficacy evokesthe maximal effect of which the biological system is capable. Thesecompounds are known as “full agonists”. They are able to elicit themaximum possible effect without occupying all the receptors, if theefficiency of coupling to the effector process is high. In contrast,“partial agonists” evoke a response but cannot evoke the maximalresponse of which the biological system is capable. They may havereasonable affinity but low intrinsic efficacy. Partial A₁ adenosineagonists may have an added benefit for chronic therapy because they willbe less likely to induce desensitization of the A₁ receptor (R. B.Clark, B. J. Knoll, R. Barber TiPS, Vol. 20 (1999) p. 279-286), and lesslikely to cause side effects.

Nomenclature

[0086] The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which R ishydrogen, R¹ is 2-hydroxycycloalkyl, R² is hydrogen, R³ is2-fluorophenyl, R⁴ and R⁵ are both hydrogen, and X and Y are bothcovalent bonds:

[0087] which is named:

[0088](4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-2-{6-[(2-hydroxycyclopentyl)amino]-purin-9-yl}oxolane-3,4-diol.

Synthetic Reaction Parameters

[0089] The terms “solvent”, “inert organic solvent” or “inert solvent”mean a solvent inert under the conditions of the reaction beingdescribed in conjunction therewith [including, for example, benzene,toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide(“DMF”), chloroform, methylene chloride (or dichloromethane), diethylether, methanol, pyridine and the like]. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert organic solvents.

[0090] The term “q.s.” means adding a quantity sufficient to achieve astated function, e.g., to bring a solution to the desired volume (i.e.,100%).

Synthesis of the Compounds of Formula I

[0091] The compounds of Formula I may be prepared starting from2,6-dichloropurine, as shown in Reaction Scheme I.

Step 1—Preparation of Formula (2)

[0092] The starting compound of formula (1) is prepared as previouslydescribed in U.S. Pat. No. 5,789,416, the complete disclosure of whichis incorporated by reference.

[0093] The compound of formula (2) is prepared conventionally from thecompound of formula (1), by reaction with 2,2-dimethoxypropane in aninert solvent, preferably dimethylformamide, in the presence of acatalytic amount of an acid catalyst, preferably p-toluenesulfonic acid,at a temperature of about 40-90° C., preferably about 70° C., for about24 -72 hours, preferably about 48 hours. When the reaction issubstantially complete, the product of formula (2) is isolated byconventional means, for example removal of the solvent under reducedpressure and purifying the residue by flash chromatography.

Step 2—Preparation of Formula (3)

[0094] The compound of formula (2) is then converted to a compound offormula (3). The compound of formula (2) is reacted with a thio compoundof formula R³SH, where R³ is as defined above, in the presence of atriphenylphosphine and diethylazodicarboxylate, in an inert solvent,preferably an ether, more preferably tetrahydrofuran.. The reaction ispreferably conducted at reflux, for about 24-100 hours, preferably about72 hours. When the reaction is substantially complete, the product offormula (3) is isolated by conventional means, for example removal ofthe solvent under reduced pressure and purifying the residue by flashchromatography.

Step 3—Preparation of Formula (4)

[0095] The 2-chloro moiety is then displaced from the compound offormula (3) by reaction with an amine of formula RR¹YNH₂, where Y is acovalent bond or alkylene, in the presence of a base, preferablytriethylamine. The reaction is carried out in an inert protic solvent,preferably ethanol, at a temperature of about reflux, for about 14-48hours, preferably about 24 hours. When the reaction is substantiallycomplete, the product of formula (4) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography of the residue on silica gel.

Step 4—Preparation of Formula I

[0096] The compound of formula (4) is then deprotected by treatment withan acid, preferably an organic acid, for example acetic acid. Thereaction is carried out in a mixture of the acid and water, at about50-100° .C, preferably about 80-90° C., for about 10-48 hours,preferably about 16 hours. When the reaction is substantially complete,the product of Formula I is isolated by conventional means, for exampleby removal of the solvent under reduced pressure, followed bychromatography of the residue on silica gel.

[0097] It should be noted that steps 2 and 3 can be carried out in thereverse order.

Alternative Synthesis of the Compounds of Formula I

[0098] Alternatively, the compounds of Formula I may be prepared asshown in Reaction Scheme II.

Step 1—Preparation of Formula (5)

[0099] The resin/compound of formula (5) is prepared from the compoundof formula (1), by reaction with dimethylacetal resin in an inertsolvent, preferably dimethylacetarnide, in the presence of a catalyticamount of an acid catalyst, preferably 10-camphorsulfonic acid, at aboutroom temperature, for about 1-7 days, preferably about 4 days. When thereaction is substantially complete, the resin/product of formula (5) isisolated by conventional means, for example filtration.

Step 2—Preparation of Formula (6)

[0100] The 2-chloro moiety is then displaced from the resin/compound offormula (5) by reaction with an amine of formula RR¹YNH₂, where Y is acovalent bond or alkylene, in the presence of a base, preferablydiisopropylethylamine. The reaction is carried out in an inert proticsolvent, preferably 1,4-dioxane, at a temperature of about 80° C. forabout 14-96 hours, preferably about 48 hours. When the reaction issubstantially complete, the resin/product of formula (6) is isolated byconventional means.

Step 3—Preparation of Formula (7)

[0101] The product of formula (6) is then converted to a resin/compoundof formula (7). The resin/compound of formula (6) is initially reactedwith a compound capable of forming a leaving group, preferablymethanesulfonyl chloride, in the presence of a base, preferablydiisopropylethylamine, at about 0° C. The mesylated product is thenreacted with a thio compound of formula R³XSH, where R³ and X are asdefined above, in an inert solvent, preferably aqueous acetonitrile. Thereaction is preferably conducted at about reflux, for about 24-100hours, preferably about 70 hours. When the reaction is substantiallycomplete, the product of formula (7) is isolated by conventional means,for example filtration.

Step 4—Preparation of Formula I

[0102] The resin/compound of formula (7) is then deprotected bytreatment with an acid, preferably an organic acid, for example 2%trifluoroacetic acid/5% methanol/methylene chloride. The reaction iscarried out at about room temperature for about 30 minutes to 10 hours,preferably about 2 hours. When the reaction is substantially complete,the product of Formula I is isolated by conventional means, for exampleextraction with an inert solvent, preferably methylene chloride, andremoval of the solvent from the extract by evaporation under reducedpressure.

Starting Materials

[0103] Compounds of formula (1) in which R² is not hydrogen may beprepared by methods well known in the art. For example, the preparationof a compound of formula (1) in which R² is trifluoromethyl is preparedas shown in Reaction Scheme III.

[0104] The preparation of a compound of formula (4) in which R² isnitrile is prepared as shown in Reaction Scheme IV.

Starting Material of Formula (e)

[0105] The starting material of formula (b) is obtained commercially(Aldrich, Milwaukee). The product of formula (e) is converted into acompound of formula (4) as shown above.

[0106] The compounds of formula (1) where R² is acyl are obtained byreacting 2-stannyl-6-chloro-2′,3′,5′-tris-t-butyldimethylsilyladenosine(K. Kato et. al. J. Org. Chem. 1997, 62, 6833-6841) with an acidchloride.

Utility, Testing and Administration General Utility

[0107] The compounds of Formula I are effective in the treatment ofconditions known to respond to administration of a partial or fullagonist of an A₁ adenosine receptor. Such conditions include, but arenot limited to, acute and chronic disorders of heart rhythm, especiallythose diseases characterized by rapid heart rate, in which the rate isdriven by abnormalities in the sinoatrial, atria, and AV nodal tissues.Such disorders include, but are not limited to, atrial fibrillation,supraventricular tachycardia and atrial flutter, congestive heartfailure, non-insulin-dependent diabetes mellitus, hyperglycemia,epilepsy (anticonvulsant activity), and neuroprotection. A₁ agonistsalso have antilipolytic effects in adipocytes that leads to a decreasedrelease of nonesterified fatty acids

Testing

[0108] Activity testing is conducted as described in those patents andliterature citations referenced above, and in the Examples below, and bymethods apparent to one skilled in the art.

Pharmaceutical Compositions

[0109] The compounds of Formula I are usually administered in the formof pharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modem Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed. (G.S. Banker & C. T. Rhodes, Eds.).

Administration

[0110] The compounds of Formula I may be administered in either singleor multiple doses by any of the accepted modes of administration ofagents having similar utilities, for example as described in thosepatents and patent applications incorporated by reference, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

[0111] One mode for administration is parental, particularly byinjection. The forms in which the novel compositions of the presentinvention may be incorporated for administration by injection includeaqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.Aqueous solutions in saline are also conventionally used for injection,but less preferred in the context of the present invention. Ethanol,glycerol, propylene glycol, liquid polyethylene glycol, and the like(and suitable mixtures thereof), cyclodextrin derivatives, and vegetableoils may also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like.

[0112] Sterile injectable solutions are prepared by incorporating thecompound of Formula I in the required amount in the appropriate solventwith various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0113] Oral administration is another route for administration of thecompounds of Formula I. Administration may be via capsule or entericcoated tablets, or the like. In making the pharmaceutical compositionsthat include at least one compound of Formula I, the active ingredientis usually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, in can be a solid, semi-solid,or liquid material (as above), which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

[0114] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents.

[0115] The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart. Controlled release drug delivery systems for oral administrationinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770;4,326,525; 4,902514; and 5,616,345. Another formulation for use in themethods of the present invention employs transdermal delivery devices(“patches”). Such transdermal patches may be used to provide continuousor discontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

[0116] The compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).The compounds of Formula I are effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 10mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg,and for parenteral administration, preferably from 10 to 700 mg of acompound of Formula I, more preferably about 50-200 mg. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

[0117] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

[0118] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

[0119] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

[0120] The following examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLE 1 Preparation of a Compound of Formula (2)

[0121] A. Preparation of a Compound of Formula (2) in which R³ isHydrogen

[0122] To a solution of2-(6-chloropurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol (acompound of formula (1)) (4.9 g, 17.1 mmol) and 2,2-dimethoxypropane(10.5 mL, 84.7 mmol) in dimethylformamide (100 mL) was addedp-toluenesulfonic acid (325 mg, 1.71 mmol). After stirring for 24 hoursat 70° C., the reaction was concentrated in vacuo and the residuepurified by flash column chromatography (70%EtOAc/Hexanes) to give6-(6-chloropurine-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol,a compound of formula (2), as an off-white solid (2). (3.8 g, 68%) ¹HNMR (CDCl3) δ1.4 (s, 3H), 1.65 (s, 3H), 3.8-4.0 (dd, 2H), 4.6 (s, 1H),5.1-5.3 (m, 2H), 6.0 (d, 1H), 8.25 (s, 1H), 8.8 (s, 1H).

[0123] B. Preparation of a Compound of Formula (2), Varying R²

[0124] Similarly, following the procedure of 1A above, but replacing2-(6-chloropurin-9-yl)-5-hydroxymethyltetrahydrofuran-3,4-diol withother compounds of formula (1), other compounds of formula (2) areprepared.

EXAMPLE 2 Preparation of a Compound of Formula (3)

[0125] A. Preparation of a Compound of Formula (3) in which R² isHydrogen, R³ is 2-Fluorophenyl, and X is a Covalent Bond

[0126] To a solution of6-(6-chloropurine-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol,a compound of formula (2) (0.48 g, 1.47 mmoles) in 20 mL oftetrahydrofuran was added triphenylphosphine (0.77 g, 2.94 mmoles) anddiethylazodicarboxylate (0.47 mL, 2.94 mmoles), and the mixture stirredfor 5 minutes. 2-Fluorothiophenol (0.31 mL, 2.94 mmoles) was then added,and the mixture was stirred under reflux. After 72 hours of reflux, thereaction was concentrated in vacuo and the residue purified by flashcolumn chromatography (20%EtOAc/Hexanes) to give1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzene,a compound of formula (3), as a clear viscous oil (3). (0.25 g, ˜40%) ¹HNMR (CDCl3) δ1.4 (s, 3H), 1.6 (s, 3H), 3.2 (m, 2H), 4.6 (t, 1H), 5.1 (m,1H), 5.5 (m, 1H), 6.0 (d, 1H), 7.0 (m, 2H), 7.2 (m, 1H), 7.4 (m, 1H),8.25 (s, 1H), 8.75 (s, 1H).

[0127] B. Preparation of a Compound of Formula (3), Varying R² and R³

[0128] Similarly, following the procedure of 2A above, but optionallyreplacing6-(6-chloropurine-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanolwith other compounds of formula (2), and optionally replacing2-fluorothiophenol with other compounds of formula R³XH, the followingcompounds of formula (3) were prepared.

[0129]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}benzene;

[0130]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2,6-dichlorobenzene;

[0131]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2,4-difluorobenzene;

[0132]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-4-fluorobenzene;

[0133]2-{[(2S,1R,⁴R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-4-methyl-1,3-thiazole;

[0134] 2-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-1,3-benzoxazole;

[0135]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-methylbenzene;

[0136]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-chlorobenzene;

[0137]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-4-chlorobenzene;

[0138]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzene;

[0139]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-3-fluorobenzene;

[0140]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-thiophene;and

[0141]1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methoxy}-2-fluorobenzene.

[0142] B. Preparation of a Compound of Formula (3), Varying R² and R³

[0143] Similarly, following the procedure of 2A above, but optionallyreplacing6-(6-chloropurine-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanolwith other compounds of formula (2), and optionally replacing2-fluorothiophenol with other compounds of formula R³XH, other compoundsof formula (3) are prepared.

EXAMPLE 3 Preparation of a Compound of Formula (4)

[0144] A. Preparation of a Compound of Formula (4) in which R isHydrogen R¹ is Cyclopentyl, R² is Hydrogen, R³ is 2-Fluorophenyl, and Xand Y are Covalent Bonds

[0145] To a solution of1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzene,a compound of formula (3), (0.125 g, 2.86 mmoles) in 10 mL of ethanoland 1 mL of triethylamine was added cyclopentylamine in excess, and themixture refluxed under nitrogen for 24 hours. The solvent was removedunder reduced pressure, and the residue was purified by preparative TLCusing 1:1 EtOAc:Hexanes to give(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine,a compound of formula (4), as a yellow oil (80mg, 56%) ¹H NMR (CDCl3)δ1.4 (s, 3H), 1.6 (s, 3H), 1.6-2.4 (m, 6H), 3.15-3.25 (m, 2H), 4.1 (bs,1H), 4.4 (t, 1H), 5.1 (m, 1H), 5.5 (m, 1H), 6.0 (d, 1H), 6.2 (bs, 1H),7.0 (m, 2H), 7.2 (m, 1H), 7.4 (m, 1H), 7.8 (s, 1H), 8.25 (s, 1H).

[0146] B. Preparation of a Compound of Formula (4), Varying R¹ R² R³,and Y

[0147] Similarly, following the procedure of 3A above, but optionallyreplacing1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzenewith other compounds of formula (3), and optionally replacingcyclopentylamine with other compounds of formula R¹YNH₂, the followingcompounds of formula (4) in which R is methyl, R¹ is2-(3,4-dimethoxyphenyl)ethyl, R² is hydrogen, and X and Y are covalentbonds were also prepared:

[0148] R³ is 2,6-dichlorophenyl;

[0149] R³ is 4-methylthiazol-2-yl;

[0150] R³ is 1,3-benzoxazol-2-yl;

[0151] 2-methylphenyl;

[0152] R³ is 2-chlorophenyl; and

[0153] R³ is 4-chlorophenyl.

[0154] C. Preparation of a Compound of Formula (4), Varing R, R² R³ andY

[0155] Similarly, following the procedure of 3A above, but optionallyreplacing1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.30]oct-2-yl]methylthio}-2-fluorobenzenewith other compounds of formula (3), and optionally replacingcyclopentylamine with other compounds of formula R¹YNH₂, other compoundsof formula (4) are prepared.

EXAMPLE 4 Preparation of a Compound of Formula I

[0156] A. Preparation of a Compound of Formula I in which R is Hydrogen,R¹ is Cyclopentyl, R² is Hydrogen, R³ is 2-Fluorophenyl, and X and Y areCovalent Bonds

[0157](9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine,a compound of formula (4) (50 mg) was dissolved in a mixture of aceticacid (8 mL) and water (2 mL) and heated at 90° C. for 16 hours. Solventswere removed under reduced pressure, and the residue was purified bypreparative TLC [methanol-dichloromethane(1:9)] to afford(4S,5S,3R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol,a compound of Formula I,. ¹H NMR (CDCl3) δ1.6-2.4 (m, 6H), 3.15-3.25 (m,2H), 4.1 (bs, 1H), 4.4-4.65 (m, 4H), 6.0 (d, 1H), 6.8 (bs, 1H), 7.05 (m,2H), 7.2 (m, 1H), 7.4 (m, 1H), 7.8 (s, 1H), 8.25 (s, 1H).

[0158] B. Preparation of a Compound of Formula I, Varying R

[0159] Similarly, following the procedure of 4A above, but replacing(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylaminewith other compounds of formula (4), the following compounds of FormulaI were made, in which R, R², R⁴ and R⁵ are hydrogen, R³ is2-fluorophenyl, X and Y are covalent bonds, and R¹ is:

[0160] cyclopentyl;

[0161] (R,R)-2-hydroxycyclopentyl;

[0162] (R,S)-2-hydroxycyclopentyl;

[0163] bicyclo[2.2.1]heptan-2-yl, 7,7-dimethylbicyclo[2.2.1]heptan-2-yl;

[0164] bicyclo[2.2.1]heptan-2-yl-3-carboxylic acid ethyl ester;

[0165] bicyclo[2.2.1]heptan-2-yl-3-carboxylic acidbicyclo[2.2.1]heptan-2-yl-3-methanol;

[0166] cyclopentyl-2-carboxylic acid ethyl ester;

[0167] cyclopentyl-2-carboxylic acid;

[0168] (R) 2-hydroxycyclohexy;l

[0169] (S) 2-hydroxycyclohexyl;

[0170] (R)-1-phenylethyl;

[0171] (S)-1-phenylethyl;

[0172] (4-fluorophenyl)methyl;

[0173] 4-trifluoromethoxyphenylmethyl;

[0174] 2,6-difluorophenylmethyl;

[0175] (3-methoxyphenyl)methyl;

[0176] (4-methoxyphenyl)methyl;

[0177] 2-benzyloxycyclopentyl;

[0178] (4-methylphenyl)ethyl;

[0179] furan-2-yl;

[0180] phenylcyclopropyl;

[0181] 3-propionic acid ethyl ester;

[0182] cyclohexyl;

[0183] 1-(4-methoxyphenyl)ethyl;

[0184] 3-trifluoromethylphenylmethyl;

[0185] 3,5-dichlorophenylmethyl;

[0186] (3 -fluorophenyl)methyl;

[0187] (2-trifluoromethylphenyl)methyl;

[0188] (4-chlorophenyl)methyl;

[0189] (2-fluorophenyl)methyl;

[0190] 2-chloro-4-fluorophenylmethyl;

[0191] 2-fluoro-4-trifluoromethylphenylmethyl;

[0192] 2,4-dichlorophenylethyl;

[0193] (R)-2-phenylpropyl;

[0194] (S)-2-phenylpropyl;

[0195] 2-(3-fluorophenyl)ethyl;

[0196] 2-(2-chlorophenyl)ethyl;

[0197] 6,6-dimethylbicyclo[3.3.1]hept-3-yl;

[0198] 4-(tert-butyl)cyclohexyl;

[0199] 2-chlorophenylmethyl;

[0200] 1-(4-methylphenyl)ethyl;

[0201] (3-methylphenyl)methyl;

[0202] (4-methylphenyl)methyl;

[0203] 2-trifluoromethyl-5-fluorophenylmethyl;

[0204] 2-chloro-3-trifluoromethylphenylmethyl;

[0205] 2,6,6-trimethylbicyclo[3.3.1]hept-3-yl;

[0206] 1-naphthylmethyl;

[0207] bicyclo[3.1.1]heptyl-3-yl;

[0208] 2-isopropyl-4-methylcyclohexyl;

[0209] 2-carboxamidocyclohexyl;

[0210] (R)-2-carboxycyclohexyl;

[0211] (S)-2-carboxycyclohexyl;

[0212] 2-hydroxymethylcyclohexyl;

[0213] 2-carboxycyclohexyl ethyl ester;

[0214] 2-carboxy-4-phenylcyclohexyl;

[0215] 2-carboxybicyclo[2.2.1]hept-5-en-3-yl; and

[0216] 2-carboxybicyclo[2.2.1]hept-3-yl ethyl ester.

[0217] Similarly, the following compounds of Formula I where R, R², R⁴and R⁵ are hydrogen, and X and Y are covalent bonds were prepared:

[0218] R³ is 4-fluorophenyl and R¹ is cyclopentyl;

[0219] R³ is 2-methylphenyl and R¹ is cyclopentyl; and

[0220] R³ is 2,4-difluorophenyl and R¹ is cyclopentyl.

[0221] C. Preparation of a Compound of Formula I, Varing R¹, R² R³, R⁴,R⁵, X and Y

[0222] Similarly, following the procedure of 4A above, or using thecombinatorial synthesis of Examples 5-8, but optionally replacing(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylaminewith other compounds of formula (4), the following compounds of FormulaI were made. R³ R¹ 2,6 dichlorophenyl 1-benzylpyrrolidin-3-yl 2,6dichlorophenyl 1-benzylpiperidin-4-yl 2,4 difluorophenyl1-benzylpyrrolidin-3-yl 4-fluorophenyl 1-benzylpiperidin-4-yl4-methyl-1,3-thiazole-2-yl 1-benzylpyrrolidin-3-yl4-methyl-1,3-thiazole-2-yl 1-benzylpiperidin-4-yl 1,3-benzoxazol-2-yl1-benzylpyrrolidin-3-yl 2-methylbenzyl 1-benzylpyrrolidin-3-yl2-methylphenyl 1-benzylpiperidin-4-yl 2-chlorophenyl1-benzylpyrrolidin-3-yl 2-chlorophenyl 1-benzylpiperidin-4-yl2-fluorophenyl 1-benzylpyrrolidin-3-yl thiophen-2-yl1-benzylpyrrolidin-3-yl 2,6 dichlorophenyl ethyl 2,6 dichlorophenylbut-1-yl 2,6 dichlorophenyl isobut-1-yl 2,6 dichlorophenyl t-butyl 2,6dichlorophenyl pent-3-yl 2,6 dichlorophenyl cyclobutyl 2,6dichlorophenyl cyclopentyl 2,6 dichlorophenyl cyclohexyl 2,6dichlorophenyl cycloheptyl 2,6 dichlorophenyl cyclooctyl 2,6dichlorophenyl (R) bicyclo[2.2.1]heptan-2-yl 2,6-dichlorophenyl3-(pyrrolid-2-one-1-yl)propyl 2,6 dichlorophenyltetrahydrofuran-2-yl-methyl 2,6 dichlorophenyl benzyl 2,6 dichlorophenyl(2-methylphenyl)methyl 2,6 dichlorophenyl (4-methylphenyl)methyl 2,6dichlorophenyl 1-phenylethyl 2,6 dichlorophenyl (2-methoxyphenyl)methyl2,6 dichlorophenyl (4-methoxyphenyl)methyl 2,6 dichlorophenyl1-cyclohexylethyl 2,6 dichlorophenyl 3-fluorobenzyl 2,6-dichlorophenyl4-fluorobenzyl 2,6 dichlorophenyl (2-trifluoromethylphenyl)methyl 2,6dichlorophenyl (2-fluoro-6-chlorophenyl)methyl 2,6-dichlorophenyl2-(3-methoxyphenyl)ethyl 2,6 dichlorophenyl 2-(4-methoxyphenyl)ethyl2,6-dichlorophenyl 2-(3-fluorophenyl)ethyl 2,6 dichlorophenyl2-(4-fluorophenyl)ethyl 2,6 dichlorophenyl 2-(3-chlorophenyl)ethyl 2,6dichlorophenyl 2,2-bis-phenylethyl 2,6 dichlorophenyl2-(thiophen-2-yl)ethyl 2,6-dichlorophenyl 3-dimethylaminopropyl 2,6dichlorophenyl 2-(morpholin-4-yl)ethyl 2,6 dichlorophenyl2-[N-ethyl-N-(3-methylphenyl)amino]ethyl 2,6-dichlorophenylpyridin-3-ylmethyl 2,6-dichlorophenyl 3-(imidazol-1-yl)propyl2,6-dichlorophenyl 1,2-dimethylpropyl 2,6 dichlorophenyl(3,4-methylenedioxyphenyl)methyl 2,6-dichlorophenyl (R)bicyclo[2.2.1]heptan-2-yl 2,6-dichlorophenyl 4-methoxyphenyl2,4-dichlorophenyl 4-ethoxyphenyl 2,4-dichlorophenyl 2-indanyl2,4-dichlorophenyl 2-fluorophenyl 2,4-difluorophenyl ethyl2,4-difluorophenyl but-1-yl 2,4-difluorophenyl 2-methylprop-1-yl2,4-difluorophenyl pent-3-yl 2,4-difluorophenyl cyclopropylmethyl2,4-difluorophenyl cyclobutyl 2,4-difluorophenyl cyclopentyl2,4-difluorophenyl cyclohexyl 2,4-difluorophenyl cycloheptyl2,4-difluorophenyl cyclooctyl 2,4-difluorophenyl (R)bicyclo[2.2.1]heptan-2-yl 2,4-difluorophenyl2,6,6-trimethylbicyclo[3.1.1]hept-3-yl 2,4-difluorophenyl2-(cyclohex-1-en-1-yl)ethyl 2,4-difluorophenyl3-(2-oxopyrrolidin-1-yl)propyl 2,4-difluorophenyltetrahydrofuran-2-yl-methyl 2,4-difluorophenyl 2-ethylhex-1-yl2,4-difluorophenyl (2-methylphenyl)methyl 2,4-difluorophenyl1-phenylethyl 2,4-difluorophenyl (2-methoxyphenyl)methyl2,4-difluorophenyl (3-methoxyphenyl)methyl 2,4-difluorophenyl(4-methoxyphenyl)methyl 2,4-difluorophenyl (R)-1-cyclohexylethyl2,4-difluorophenyl (S)-1-cyclohexylethyl 2,4-difluorophenyl(2-fluorophenyl)methyl 2,4-difluorophenyl (3-fluorophenyl)methyl2,4-difluorophenyl (4-fluorophenyl)methyl 2,4-difluorophenyl(4-chlorophenyl)methyl 2,4-difluorophenyl 2-phenylethyl2,4-difluorophenyl (2,4-dimethoxyphenyl)methyl 2,4-difluorophenyl2-(3-fluorophenyl)ethyl 2,4-difluorophenyl 2-(4-fluorophenyl)ethyl2,4-difluorophenyl 2-(3-chlorophenyl)ethyl 2,4-difluorophenyl2-(2,2-bisphenyl)ethyl 2,4-difluorophenyl 3-phenylpropyl2,4-difluorophenyl 2-(thiophen-2-yl)ethyl 2,4-difluorophenyl3,3-bisphenylpropyl 2,4-difluorophenyl2,2-dimethyl-3-(dimethylamino)propyl 2,4-difluorophenylpyridin-2-yl-methyl 2,4-difluorophenyl pyridin-3-yl-methyl2,4-difluorophenyl 3-(imidazol-1-yl)propyl 2,4-difluorophenyl(3,4-methylenedioxyphenyl)methyl 2,4-difluorophenyl (R)bicyclo[2.2.1]heptan-2-yl 2,4-difluorophenyl phenyl 2,4-difluorophenyl4-methoxyphenyl 2,4-difluorophenyl 4-phenoxyphenyl 2,4-difluorophenyl2-fluorophenyl 2,4-difluorophenyl 4-chlorophenyl 4-fluorophenyl but-1-yl4-fluorophenyl sec butyl-1-yl 4-fluorophenyl t-butyl 4-fluorophenylpent-3-yl 4-fluorophenyl cyclopropylmethyl 4-fluorophenyl cyclobutyl4-fluorophenyl cyclopentyl 4-fluorophenyl cyclohexyl 4-fluorophenylcycloheptyl 4-fluorophenyl cyclooctyl 4-fluorophenyl3,3,5-trimethylcyclohexyl 4-fluorophenyl (R) bicyclo[2.2.1]heptan-2-yl4-fluorophenyl 2,6,6-trimethylbicyclo[3.1.1]heptanyl 4-fluorophenyl2-(cyclohex-1-en-1-yl)ethyl 4-fluorophenyl 2-ethylhex-3-yl4-fluorophenyl phenyl 4-fluorophenyl (2-methylphenyl)methyl4-fluorophenyl (3-methoxyphenyl)methyl 4-fluorophenyl 1-cyclohexylethyl4-fluorophenyl (4-fluorophenyl)methyl 4-fluorophenyl(4-chlorophenyl)methyl 4-fluorophenyl (2-trifluoromethylphenyl)methyl4-fluorophenyl 2-phenylethyl 4-fluorophenyl 2-(3-methoxyphenyl)ethyl4-fluorophenyl 2-(4-methoxyphenyl)ethyl 4-fluorophenyl2-(3-fluorophenyl)ethyl 4-fluorophenyl 2-(3-chlorophenyl)ethyl4-fluorophenyl 3-phenylpropyl 4-fluorophenyl thiophen-2-ylmethyl4-fluorophenyl 2,2-dimethyl-3-(dimethylamino)propyl 4-fluorophenyl2-(morpholin-4-yl)ethyl- 4-fluorophenyl2-[N-ethyl-N-(3-methylphenyl)]aminoethyl 4-fluorophenylpyridin-2-yl-methyl 4-fluorophenyl pyridin-3-ylmethyl 4-fluorophenylpyridin-4-yl-methyl 4-fluorophenyl 3-(imidazol-1-yl)propyl4-fluorophenyl (3,4-methylenedioxyphenyl)methyl 4-fluorophenyl R)bicyclo[2.2.1]heptanyl 4-fluorophenyl phenyl 4-fluorophenyl4-methoxyphenyl 4-fluorophenyl 4-ethoxyphenyl 4-fluorophenyl4-phenoxyphenyl 4-methyl-1,3-thiazole ethyl 4-methyl-1,3-thiazolebut-1-yl 4-methyl-1,3-thiazole sec but-1-yl 4-methyl-1,3-thiazolet-butyl 4-methyl-1,3-thiazole pent-3-yl 4-methyl-1,3-thiazolecyclopropylmethyl 4-methyl-1,3-thiazole cyclobutyl 4-methyl-1,3-thiazolecyclopentyl 4-methyl-1,3-thiazole cyclohexyl 4-methyl-1,3-thiazolecycloheptyl 4-methyl-1,3-thiazole 3,3,5 trimethylcyclohexyl4-methyl-1,3-thiazole (R) bicyclo[2.2.1]heptan-2-yl4-methyl-1,3-thiazole 2-(cyclohex-1-en-1-yl)ethyl 4-methyl-1,3-thiazole3-(2-oxopyrrolidin-1-yl)propyl 4-methyl-1,3-thiazole phenyl4-methyl-1,3-thiazole (2-methylphenyl)methyl 4-methyl-1,3-thiazole(3-methylphenyl)methyl 4-methyl-1,3-thiazole 1-phenylethyl4-methyl-1,3-thiazole (3-methoxyphenyl)methyl 4-methyl-1,3-thiazole(4-methoxyphenyl)methyl 4-methyl-1,3-thiazole (2-fluorophenyl)methyl4-methyl-1,3-thiazole (4-chlorophenyl)methyl 4-methyl-1,3-thiazole(2-trifluoromethylphenyl)methyl 4-methyl-1,3-thiazole(3,4-dichlorophenyl)methyl 4-methyl-1,3-thiazole 2-phenylethyl4-methyl-1,3-thiazole 2-(3-methoxyphenyl)ethyl 4-methyl-1,3-thiazole(4-methoxyphenyl)methyl 4-methyl-1,3-thiazole 2-(3-fluorophenyl)ethyl4-methyl-1,3-thiazole 2-(4-fluorophenyl)ethyl 4-methyl-1,3-thiazole2-(2-chlorophenyl)ethyl 4-methyl-1,3-thiazole 2-(3-chlorophenyl)ethyl4-methyl-1,3-thiazole 2,2-bisphenylethyl 4-methyl-1,3-thiazole2-(thiophen-2-yl)ethyl 4-methyl-1,3-thiazole 3,3-bisphenylpropyl4-methyl-1,3-thiazole 4-phenylbut-2-yl 4-methyl-1,3-thiazole3-(dimethylamino)propyl 4-methyl-1,3-thiazole 2-(morpholin-4-yl)ethyl-4-methyl-1,3-thiazole 2-[2-ethyl-2-(3-methylphenyl)amino]ethyl4-methyl-1,3-thiazole pyridin-3-ylmethyl 4-methyl-1,3-thiazolepyridin-4-ylmethyl 4-methyl-1,3-thiazole 3-(imidazol-1-yl)propyl4-methyl-1,3-thiazole 3-methylbut-2-yl 4-methyl-1,3-thiazole(3,4-methylenedioxyphenyl)methyl 4-methyl-1,3-thiazole (S)bicyclo[2.2.1]heptan-2-yl 4-methyl-1,3-thiazole phenyl1,3-benzoxazol-2-yl pent-3-yl 1,3-benzoxazol-2-yl cyclopropylmethyl1,3-benzoxazol-2-yl cyclopentyl 1,3-benzoxazol-2-yl cycloheptyl1,3-benzoxazol-2-yl cyclooctyl 1,3-benzoxazol-2-yl3,3,5-trimethylcyclohexyl 1,3-benzoxazol-2-yl3-(2-oxopyrrolidin-1-yl)propyl 1,3-benzoxazol-2-yltetrahydrofuran-2-yl-methyl 1,3-benzoxazol-2-yl 2-ethylhex-1-yl1,3-benzoxazol-2-yl phenyl 1,3-benzoxazol-2-yl (2-methylphenyl)methyl1,3-benzoxazol-2-yl (4-methylphenyl)methyl 1,3-benzoxazol-2-yl1-phenylethyl 1,3-benzoxazol-2-yl (2-methoxyphenyl)methyl1,3-benzoxazol-2-yl (3-methoxyphenyl)methyl 1,3-benzoxazol-2-yl(4-methoxyphenyl)methyl 1,3-benzoxazol-2-yl 1-cyclohexylethyl1,3-benzoxazol-2-yl (3-fluorophenyl)methyl 1,3-benzoxazol-2-yl(4-fluorophenyl)methyl 1,3-benzoxazol-2-yl(2-fluoro-6-chlorophenyl)methyl 1,3-benzoxazol-2-yl(2,4-dichlorophenyl)methyl 1,3-benzoxazol-2-yl 2-phenylethyl1,3-benzoxazol-2-yl 2-(3-methoxyphenyl)ethyl 1,3-benzoxazol-2-yl2-(4-methoxyhenyl)ethyl 1,3-benzoxazol-2-yl 2-(4-fluorophenyl)ethyl1,3-benzoxazol-2-yl 2-(2-chlorophenyl)ethyl 1,3-benzoxazol-2-yl2-(3-chlorophenyl)ethyl 1,3-benzoxazol-2-yl 2,2-bis-phenylethyl1,3-benzoxazol-2-yl 3-phenylpropyl 1,3-benzoxazol-2-yl2-(thiophen-2-yl)ethyl 1,3-benzoxazol-2-yl 3,3-bisphenylpropyl1,3-benzoxazol-2-yl 2-(morpholin-4-yl)ethyl- 1,3-benzoxazol-2-yl2-[N-ethyl-N-(3-methylphenyl)amino]ethyl 1,3-benzoxazol-2-yl3-methylbut-2-yl 1,3-benzoxazol-2-yl (S) bicyclo[2.2.1]heptan-2-yl1,3-benzoxazol-2-yl phenyl 1,3-benzoxazol-2-yl 4-ethoxyphenyl1,3-benzoxazol-2-yl 2-indanyl 2-methylphenyl ethyl 2-methylphenylbut-1-yl 2-methylphenyl sec-but-1-yl 2-methylphenyl pent-3-yl2-methylphenyl cyclopropylmethyl 2-methylphenyl cyclopentyl2-methylphenyl cycloheptyl 2-methylphenyl 3,3,5-trimethylcyclohexyl2-methylphenyl (S) bicyclo[2.2.1]heptan-2-yl 2-methylphenyl2,6,6-trimethylbicyclo[3.1.1]hept-3-yl 2-methylphenyl2-(cyclohex-1-en-1-yl)ethyl 2-methylphenyl 3-(pyrrolid-2-one-1-yl)propyl2-methylphenyl 2-ethylhex-1-yl 2-methylphenyl (2-methylphenyl)methyl2-methylphenyl (3-methylphenyl)methyl 2-methylphenyl 1-phenylethyl2-methylphenyl (4-methoxyphenyl)methyl 2-methylphenyl(R)-1-cyclohexylethyl 2-methylphenyl (2-trifluoromethylphenyl)methyl2-methylphenyl (3,4-dichlorophenyl)methyl 2-methylphenyl2-(3-fluorophenyl)ethyl 2-methylphenyl 2-(4-fluorophenyl)ethyl2-methylphenyl 2-(2-chlorophenyl)ethyl 2-methylphenyl2-(3-chlorophenyl)ethyl 2-methylphenyl 3-phenylpropyl 2-methylphenyl2,2-bisphenylethyl 2-methylphenyl 3-dimethylaminopropyl 2-methylphenyl2-(morpholin-4-yl)ethyl- 2-methylphenyl2-[N-ethyl-N-(3-methylphenyl)amino]ethyl 2-methylphenylpyridin-2-yl-methyl 2-methylphenyl pyridin-3-yl-methyl 2-methylphenylpyridin-4-yl-methyl 2-methylphenyl 3-propylimidazol-1-yl 2-methylphenyl3,4-methylenedioxyphenylmethyl 2-methylphenyl (R)bicyclo[2.2.1]heptan-2-yl 2-methylphenyl 4-methoxyphenyl 2-methylphenyl4-phenoxyphenyl 2-methylphenyl 2-indanyl 2-chlorophenyl ethyl2-chlorophenyl but-1-yl 2-chlorophenyl pent-3-yl 2-chlorophenylcyclopropylmethyl 2-chlorophenyl cyclopentyl 2-chlorophenyl cyclohexyl2-chlorophenyl cycloheptyl 2-chlorophenyl 3,3,5 trimethylhexyl2-chlorophenyl 2-(cyclohex-1-en-1-yl)ethyl 2-chlorophenyl3-(pyrrolid-2-one-1-yl)propyl 2-chlorophenyl tetrahydrofuran-2-ylmethyl2-chlorophenyl 2-ethylhex-1-yl 2-chlorophenyl 2-(4-methoxypheny)ethyl2-chlorophenyl 2-(3-fluorophenyl)ethyl 2-chlorophenyl2-(4-fluorophenyl)ethyl 2-chlorophenyl 2-(2-chlorophenyl)ethyl2-chlorophenyl 2-(3-chlorophenyl)ethyl 2-chlorophenyl 2,2 bisphenylethyl2-chlorophenyl 3-phenylpropyl 2-chlorophenyl 2-(thiophen-2-yl)ethyl2-chlorophenyl 3,3-bisphenylpropyl 2-chlorophenyl 4-phenylbut-2-yl2-chlorophenyl 3-dimethylaminopropyl 2-chlorophenyl2-(morpholin-4-yl)ethyl- 2-chlorophenyl2-[N-ethyl-N-(3-methylphenyl)amino]ethyl 2-chlorophenylpyridin-2-yl-methyl 2-chlorophenyl pyridin-4-yl-methyl 2-chlorophenyl3-(imidazol-3-yl)propyls 2-chlorophenyl 1,2-dimethylpropyl2-chlorophenyl pentyl-3-yl 2-chlorophenyl 3,4-methylenedioxyphenylmethyl2-chlorophenyl (S) bicyclo[2.2.1]heptan-2-yl 2-chlorophenyl4-methoxyphenyl 2-chlorophenyl 4-ethoxyphenyl 2-chlorophenyl4-phenoxyphenyl 2-chlorophenyl 2-indanyl 2-chlorophenyl 4-chlorophenyl2-chlorophenyl tetrahydropyran-4-yl 2-chlorophenyl phenylmethyl2-chlorophenyl (2-methylphenyl)methyl 2-chlorophenyl(3-methylphenyl)methyl 2-chlorophenyl 1-phenylethyl 2-chlorophenyl(2-methoxyphenyl)methyl 2-chlorophenyl (3-methoxyphenyl)methyl2-chlorophenyl (4-methoxyphenyl)methyl 2-chlorophenyl1-(cyclohexyl)ethyl 2-chlorophenyl (3-fluorophenyl)methyl 2-chlorophenyl(3-chlorophenyl)methyl 2-chlorophenyl (2-trifluoromethylphenyl)methyl2-chlorophenyl (2-fluoro-6-chlorophenyl)methyl 2-chlorophenyl2-phenylethyl 2-chlorophenyl 2-(3-methoxyphenyl)ethyl 2-chlorophenylethyl 4-chlorophenyl isobut-1-yl 4-chlorophenyl t-butyl 4-chlorophenylpent-3-yl 4-chlorophenyl cyclopropylmethyl 4-chlorophenyl cyclopentyl4-chlorophenyl cyclohexyl 4-chlorophenyl cycloheptyl 4-chlorophenyl3,3,5 trimethylcyclohexyl 4-chlorophenyl (S) bicyclo[2.2.1]heptan-2-yl4-chlorophenyl 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl 4-chlorophenylcyclohexylethyl 4-chlorophenyl tetrahydrofuran-2-yl-methyl4-chlorophenyl 2-ethylhex-1-yl 4-chlorophenyl phenylmethyl4-chlorophenyl (2-methylphenyl)methyl 4-chlorophenyl(3-methylphenyl)methyl 4-chlorophenyl (4-methylphenyl)methyl4-chlorophenyl 2-phenylethyl 4-chlorophenyl (2-methoxyphenyl)methyl4-chlorophenyl (3-methoxyphenyl)methyl 4-chlorophenyl(4-methoxyphenyl)methyl 4-chlorophenyl (R)-1-cyclohexlethyl4-chlorophenyl (S)-1-cyclohexylethyl 4-chlorophenyl(2-fluorophenyl)methyl 4-chlorophenyl (3-fluorophenyl)methyl4-chlorophenyl (4-chlorophenyl)methyl 4-chlorophenyl(2-fluoro-6-chlorophenyl)methyl 4-chlorophenyl(2,4-dichlorophenyl)methyl 4-chlorophenyl 2-phenylethyl 4-chlorophenyl2-(3-methoxyhenyl)ethyl 4-chlorophenyl 2-(3-fluorophenyl)ethyl4-chlorophenyl 2-(4-fluorophenyl)ethyl 4-chlorophenyl2-(2-chlorophenyl)ethyl 4-chlorophenyl 2-(3-chlorophenyl)ethyl4-chlorophenyl 2,2-bis-phenylethyl 4-chlorophenyl 3-phenylpropyl4-chlorophenyl 2-(thiophene-2-yl)ethyl 4-chlorophenyl 3,3bisphenylpropyl 4-chlorophenyl 4-phenylbut-2-yl 4-chlorophenylN-ethyl-N-(3-methylphenyl)ethylamino 4-chlorophenyl phenyl4-chlorophenyl 4-methoxyphenyl 4-chlorophenyl 4-ethoxyphenyl4-chlorophenyl 4-phenoxyphenyl 4-chlorophenyl ethyl 2-fluorophenylbut-1-yl 2-fluorophenyl isobut-1-yl 2-fluorophenyl t-butyl2-fluorophenyl pent-3-yl 2-fluorophenyl cyclopropylmethyl 2-fluorophenylcyclobutyl 2-fluorophenyl cyclopentyl 2-fluorophenyl cyclohexyl2-fluorophenyl cycloheptyl 2-fluorophenyl (S) bicyclo[2.2.1]heptan-2-yl2-fluorophenyl 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl 2-fluorophenyl2-(cyclohex-1-en-1-yl)ethyl 1 2-fluorophenyl3-(pyrrolid-2-one-1-yl)propyl 2-fluorophenyl tetrahydrofuran-2-yl-methyl2-fluorophenyl 2-ethylhex-1-yl 2-fluorophenyl benzyl 2-fluorophenyl(2-methylphenyl)methyl 2-fluorophenyl (3-methylphenyl)methyl2-fluorophenyl (4-methylphenyl)methyl 2-fluorophenyl 1-phenylethyl2-fluorophenyl (2-methoxyphenyl)methyl 2-fluorophenyl(3-methoxyphenyl)methyl 2-fluorophenyl (4-methoxyphenyl)methyl2-fluorophenyl (R)-1-(cyclohexyl) ethyl 2-fluorophenyl(S)-1-(cyclohexyl) ethyl 2-fluorophenyl (2-fluorophenyl)methyl2-fluorophenyl (3-fluorophenyl)methyl 2-fluorophenyl(4-fluorophenyl)methyl 2-fluorophenyl (4-chlorophenyl)methyl2-fluorophenyl (2-trifluoromethylphenyl)methyl 2-fluorophenyl(2-fluoro-6-chlorophenyl)methyl 2-fluorophenyl 2-phenylethyl2-fluorophenyl 2-(3-methoxyphenyl)ethyl 2-fluorophenyl2-(4-methoxyphenyl)ethyl 2-fluorophenyl 2-(3-fluorophenyl)ethyl2-fluorophenyl 2-(4-fluorophenyl)ethyl 2-fluorophenyl2-(3-chlorophenyl)ethyl 2-fluorophenyl 2,2 bisphenylmethyl2-fluorophenyl 3-phenylpropyl 2-fluorophenyl 2-(thiophen-2-yl)ethyl2-fluorophenyl (S)-(3,3 bisphenyl)propyl 2-fluorophenyl 4-phenylbut-2-yl2-fluorophenyl 2-[N-ethyl-N-(3-methylphenyl)amino]ethyl 2-fluorophenylpyridin-2-ylmethyl 2-fluorophenyl (3,4-methylenedioxyphenyl)methyl2-fluorophenyl (S) bicyclo[2.2.1]heptan-2-yl 2-fluorophenyl phenyl2-fluorophenyl 4-methoxyphenyl 2-fluorophenyl 4-ethoxyphenyl2-fluorophenyl 4-phenoxyphenyl 2-fluorophenyl 2-indanyl 2-fluorophenyl4-chlorophenyl 2-fluorophenyl but-1-yl 3-fluorophenyl isobut-1-yl3-fluorophenyl t-butyl 3-fluorophenyl pent-3-yl 3-fluorophenylcyclopropylmethyl 3-fluorophenyl cyclobutyl 3-fluorophenyl cyclopentyl3-fluorophenyl cyclohexyl 3-fluorophenyl cyclohept-3-yl 3-fluorophenylcyclooctyl 3-fluorophenyl 3,3,5-trimethylcyclohexyl 3-fluorophenyl2-ethylhex-1-yl 3-fluorophenyl benzyl 3-fluorophenyl(2-methylphenyl)methyl 3-fluorophenyl (3-methylphenyl)methyl3-fluorophenyl (4-methylphenyl)methyl 3-fluorophenyl 1-phenylethyl3-fluorophenyl (4-methoxyphenyl)methyl 3-fluorophenyl(2-fluorophenyl)methyl 3-fluorophenyl (3-fluorophenyl)methyl3-fluorophenyl (2,4-dichlorophenyl)methyl 3-fluorophenyl(3,4-dichlorophenyl)methyl 3-fluorophenyl 2-(3-methoxyphenyl)ethyl3-fluorophenyl 2-(4-methoxyhenyl)ethyl 3-fluorophenyl2-(3-fluorophenyl)ethyl 3-fluorophenyl 2-(4-fluorophenyl)ethyl3-fluorophenyl 2-(3-chlorophenyl)ethyl 3-fluorophenyl 2,2-bisphenylethyl3-fluorophenyl 3-phenylpropyl 3-fluorophenyl 3,3-bisphenylpropyl3-fluorophenyl 4-phenylbut-2-yl 3-fluorophenyl 2-(morpholin-4-yl)ethyl-3-fluorophenyl 2-(N-ethyl-N-phenyl)aminoethyl 3-fluorophenylpyridin-2-ylmethyl 3-fluorophenyl pyridin-2-ylmethyl 3-fluorophenyl1,2-dimethylpropyl 3-fluorophenyl (3,4-methylenedioxyphenyl)methyl3-fluorophenyl (R) bicyclo[2.2.1]heptan-2-yl 3-fluorophenyl phenyl3-fluorophenyl 4-methoxyphenyl 3-fluorophenyl 4-ethoxyphenyl3-fluorophenyl 4-phenoxyphenyl thiophene-2-yl t-butyl thiophene-2-ylpent-3-yl thiophene-2-yl cyclopropylmethyl thiophene-2-yl3,3,5-trimethylcyclohexane thiophene-2-yl (S) bicyclo[2.2.1]heptan-2-ylthiophene-2-yl tetrahydrofuran-2-ylmethyl thiophene-2-yl 2-ethylhex-1-ylthiophene-2-yl benzyl thiophene-2-yl (2-methylphenyl)methylthiophene-2-yl (3-methylphenyl)methyl thiophene-2-yl(4-methylphenyl)methyl thiophene-2-yl (2-methoxyphenyl)methylthiophene-2-yl (3-methoxyphenyl)methyl thiophene-2-yl(4-methoxyphenyl)methyl thiophene-2-yl 1-cyclohexylethyl thiophene-2-yl(2-fluorophenyl)methyl thiophene-2-yl (3-fluorophenyl)methylthiophene-2-yl (4-fluorophenyl)methyl thiophene-2-yl 2-phenylethylthiophene-2-yl 2-(4-methoxyphenyl)ethyl thiophene-2-yl2-(3-fluorophenyl)ethyl thiophene-2-yl2-[N-ethyl-N-(3-methylphenyl)amino]ethyl thiophene-2-yl phenyl3-fluorophenyl ethyl phenyl but-1-yl phenyl isobut-1-yl phenyl t-butylphenyl pentyl-3-yl phenyl cyclopropylmethyl phenyl cyclobutyl-1-ylphenyl cyclopentyl phenyl cyclohexyl phenyl cyclohept-3-yl phenyl3,3,5-trimethylcyclohexyl phenyl (R) bicyclo[2.2.1]heptan-2-yl phenyl2,6,6-trimethylbicyclo[3.1.1]hept-3-yl phenyl2-(cyclohex-1-en-1-yl)ethyl phenyl 3-(2-oxopyrrolidin-1-yl)propyl phenyltetrahydrofuran-2-ylmethyl phenyl 2-ethylhex-1-yl phenyl phenyl phenyl(2-methylphenyl)methyl phenyl (3-methylphenyl)methyl phenyl(4-methylphenyl)methyl phenyl 1-phenylethyl phenyl(4-methoxyphenyl)methyl phenyl (R)-1-cyclohexylethyl phenyl(S)-1-cyclohexylethyl phenyl (2-fluorophenyl)methyl phenyl(3-fluorophenyl)methyl phenyl (4-fluorophenyl)methyl phenyl(4-chlorophenyl)methyl phenyl (2-trifluoromethylphenyl)methyl phenyl(2-fluoro-6-chlorophenyl)methyl phenyl (2,4-dichlorophenyl)methyl phenyl(3,4-dichlorophenyl)methyl phenyl 2-phenylethyl phenyl2-(3-methoxyphenyl)ethyl phenyl 2-(3-fluorophenyl)ethyl phenyl2-(4-fluorophenyl)ethyl phenyl 2-(3-chlorophenyl)ethyl phenyl2,2-bisphenylethyl phenyl phenylcyclopropyl phenyl 3-phenylpropyl phenyl2-(thiophen-2-yl)ethyl phenyl 3-dimethylaminopropyl phenyl2-(morpholin-4-yl)ethyl phenyl 1-benzylpiperidin-4-yl phenylpyridin-2-yl-methyl phenyl pyridin-4-yl-methyl phenyl3-(imidazol-1-yl)propyl phenyl (3,4-methylenedioxyphenyl)methyl phenylphenyl phenyl 4-methoxyphenyl phenyl 4-ethoxyphenyl phenyl4-phenoxyphenyl phenyl 2-indanyl Combination of R, R¹ and the nitrogenR³ atom to which they are attached 2,4-dichlorophenyl piperidin-1-yl2,4-dichlorophenyl 2-ethypiperidin-1-yl 2,4-dichlorophenyl4-(piperidin-1-yl)piperidin-1-yl 2,4-dichlorophenyl1,2,3,4-tetrahydro-isoquinolin-2-yl 2,4-dichlorophenyl morpholin-4-yl2,4-difluorophenyl 4-methylpiperazin-1-yl 2,4-difluorophenylpyrrolidin-1-yl 2,4-difluorophenyl 4-benzylpiperazin-1-yl2,4-difluorophenyl piperidin-1-yl 2,4-difluorophenyl4-(piperidin-1-yl)piperidin-1-yl 2,4-difluorophenyl1,2,3,4-tetrahydro-isoquinolin-2-yl 2,4-difluorophenyl morpholin-4-yl2,4-difluorophenyl 4-methylpiperazin-1-yl 4-fluorophenyl4-benzylpiperazin-1-yl 4-fluorophenyl piperidin-1-yl 4-fluorophenyl2-ethylpiperidin-1-yl 4-fluorophenyl 4-benzylpiperidin-1-yl4-fluorophenyl 4-(piperidin-1-yl)piperidin-1-yl 4-fluorophenyl1,2,3,4-tetrahydro-isoquinolin-2-yl 4-fluorophenyl morpholin-4-yl4-fluorophenyl 4-phenlypiperazin-1-yl 4-methyl-1,3-thiazol-2-ylpyrrolidin-1-yl 4-methyl-1,3-thiazol-2-yl 4-benzylpiperazin-1-yl4-methyl-1,3-thiazol-2-yl piperidin-1-yl 4-methyl-1,3-thiazol-2-yl4-benzylpiperidin-1-yl 4-methyl-1,3-thiazol-2-yl4-(piperidin-1-yl)piperidin-1-yl 4-methyl-1,3-thiazol-2-yl1,2,3,4-tetrahydro-isoquinolin-2-yl 4-methyl-1,3-thiazol-2-ylmorpholin-4-yl 4-methyl-1,3-thiazol-2-yl 4-methylpiperazino-1-yl4-methyl-1,3-thiazol-2-yl 4-phenylpiperazin-1-yl 1,3-benzoxazol-2-ylpyrrolidin-1-yl 1,3-benzoxazol-2-yl 2-ethylpiperidin-1-yl1,3-benzoxazol-2-yl 4-benzylpiperidin-1-yl 1,3-benzoxazol-2-ylmorpholin-4-yl 1,3-benzoxazol-2-yl 4-methylpiperazin-1-yl 2-methylphenylpyrrolidin-1-yl 2-methylphenyl piperidin-1-yl 2-methylphenyl2-ethylpiperidin-1-yl 2-methylphenyl 4-benzylpiperidin-1-yl2-methylphenyl 4-(piperidin-1-yl)piperidin-1-yl 2-methylphenyl1,2,3,4-tetrahydro-isoquinolin-2-yl 2-methylphenyl morpholin-4-yl2-methylphenyl 4-(3,4-dichlorophenyl)piperazin-1-yl 2-methylphenyl4-methylpiperazin-1-yl 2-methylphenyl 4-phenylpiperazin-1-yl2-methylphenyl pyrrolidin-1-yl 2-chlorophenyl 4-benzylpiperazin-1-yl2-chlorophenyl piperidin-1-yl 2-chlorophenyl 2-ethylpiperidin-1-yl2-chlorophenyl 4-benzylpiperidine-1-yl 2-chlorophenyl4-(piperidin-1-yl)piperidin-1-yl 2-chlorophenyl1,2,3,4-tetrahydro-isoquinolin-2-yl 2-chlorophenyl morpholin-4-yl2-chlorophenyl 4-(3,4-dichlorophenyl)piperazin-1-yl 2-chlorophenyl4-methylpiperazin-1-yl 2-chlorophenyl 4-phenylpiperazin-1-yl4-chlorophenyl pyrrolidin-1-yl 4-chlorophenyl 4-benzylpiperazin-1-yl4-chlorophenyl piperidin-1-yl 4-chlorophenyl 2-ethylpiperidin-1-yl4-chlorophenyl 4-(piperidin-1-yl)piperidin-1-yl 4-chlorophenyl1,2,3,4,-tetrahydro-isoquinolin-2-yl 4-chlorophenyl morpholin-4-yl4-chlorophenyl 4-phenylpiperazin-1-yl 2-fluorophenyl pyrrolidin-1-yl2-fluorophenyl 4-benzylpiperazin-1-yl 2-fluorophenyl piperidin-1-yl2-fluorophenyl 2-ethylpiperidin-1-yl 2-fluorophenyl morpholin-4-yl2-fluorophenyl 4-phenylpiperazin-1-yl 2-fluorophenyl pyrrolidin-1-yl2-fluorophenyl 4-benzylpiperazin-1-yl 3-fluorophenyl piperidin-1-yl3-fluorophenyl 4-benzylpiperidin-1-yl 3-fluorophenyl1,2,3,4-tetrahydro-isoquinolin-2-yl 3-fluorophenyl morpholin-4-yl3-fluorophenyl 4-methylpiperazin-1-yl 3-fluorophenyl4-(piperidin-1-yl)piperidin-1-yl thiophen-2-yl 4-phenylpiperazin-1-ylthiophen-2-yl 2-ethylpiperidin-1-yl phenyl pyrrolidin-1-yl phenyl4-benzylpiperazin-1-yl phenyl piperidin-1-yl phenyl2-ethylpiperidin-1-yl phenyl 4-phenylpiperidin-1-yl phenyl4-(piperidin-1-yl)piperidin-1-yl phenyl morpholin-4-yl phenyl4-(3,4-dichlorophenyl)piperazin-1-yl

[0223] The following compounds of Formula I in which R is methyl, R¹ is2-(3,4-dimethoxyphenyl)ethyl, R² is hydrogen, and X and Y are covalentbonds were also prepared:

[0224] R³ is 2,6-dichlorophenyl;

[0225] R³ is 4-methylthiazol-2-yl;

[0226] R³ is 1,3-benzoxazol-2-yl;

[0227] 2-methylphenyl;

[0228] R³ is 2-chlorophenyl; and

[0229] R³ is 4-chlorophenyl.

[0230] D. Preparation of a Compound of Formula I,. Varying R¹, R² R³,R⁴, R⁵, X and Y

[0231] Similarly, following the procedure of 4A above, but optionallyreplacing(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylaminewith other compounds of formula (4), other compounds of Formula I aremade.

[0232] Compounds of Formula I were alternatively made in a combinatorialfashion, as shown in Reaction Scheme II above. Examples 5-8 detail thepreparation of a single compound using this technology, but the processwas utilized to provide parallel syntheses of multiple compounds ofFormula I in a combinatorial manner.

EXAMPLE 5 Preparation of a Compound of Formula (5)

[0233] A. Preparation of a Compound of Formula (5) in which R² isHydrogen

[0234] p-Benzyloxybenzaldehyde polystyrene resin (1) (100 g, 3.0 mmol/g,0.3 mol, 150-300 μm, Polymer Labs) was suspended in drytrimethylorthoformate (1 L). p-Toluenesulfonic acid monohydrate (5.70 g,0.03 mol, 0.1 eq) was added and the suspension shaken at roomtemperature for 48 hours. Triethylamine (60 mL) was added, and the resinwas promptly filtered, washed 4× with methylene chloride containing 1%triethylamine, and dried under vacuum for 24 hours to afford thedimethylacetal resin Dimethylacetal resin (20.0 g, 3 mmol/g, 60.0 mmol)was suspended in anhydrous N,N-dimethylacetamide (300 mL), and treatedsequentially with the riboside of formula (1) (34.4 g, 120 mmol, 2 eq)and 10-camphorsulfonic acid (2.78 g, 12.0 mmol, 0.2 eq.). The mixturewas shaken at 200 rpm at room temperature for 96 hours. Triethylamine(4.2 mL, 30.0 mmol, 0.5 eq) was then added and the resin promptlyfiltered, washed once with N,N-dimethylacetamide, washed with fouralternating cycles of methylene chloride containing 1% Et₃N and MeOHcontaining 1% triethylamine, and finally by three washes with methylenechloride containing 1% triethylamine. The recovered resin was driedunder vacuum for 48 hours to provide the resin-bound riboside of formula(5).

EXAMPLE 6 Preparation of a Compound of Formula (6)

[0235] A. Preparation of a Compound of Formula (6) in which R and R² areHydrogen, Y is a Covalent Bond, and R¹ is Cyclopentyl

[0236] In a reaction vessel was placed the resin-bound riboside offormula (5) (30 mg resin; resin loading 1.5 mmol/g) suspended inanhydrous 1,4-dioxane (30 mL). Diisopropylethylamine (2.4 mL, 13.5 mmol,20 eq) and excess cyclopentylamine were then added. The reaction vesselwas heated at 80° C. for 48 hours with no stirring or agitation. Aftercooling to room temperature the solvent was removed, and methanolcontaining 1% triethylamine (50 mL) was added to shrink the resin. Theproduct was washed with four alternating cycles of methanol containing1% triethylamine and methylene chloride containing 1% triethylamine, anddried overnight in vacuo to provide the resin-bound compound of formula(6).

EXAMPLE 7 Preparation of a Compound of Formula (7)

[0237] A. Preparation of a Compound of Formula (7) in which R and R² areHydrogen, Y is a Covalent Bond, and R¹ is Cyclopentyl and R³ is2-Flurophenyl

[0238] The product from Example 6 was suspended in anhydrous pyridine (2mL) and treated with diisopropylethylamine (0.13 mL). After cooling to0° C., methanesulfonyl chloride (0.035 mL, 337 mmol) was added dropwise.The reaction mixture was agitated regularly by hand during the addition.After 90 minutes the reaction mixture was warmed to room temperature andshaken for 24 hours. After removal of the reaction mixture, the productwas rinsed with anhydrous methylene chloride containing 1% triethylamineand treated with methanol containing 1% triethylamine to shrink theresin, to provide a mesylated derivative of the resin-bound compound offormula (6).

[0239] The mesylate was then suspended in acetonitrile (1.5 mL) andtreated with excess diisopropylethylamine (0.16 mL) followed by water(0.7 mL) and 2-fluorothiophenol (45 mmol). The reaction vessel waswarmed to approximately 80° C. without agitation for 65 hours. Theproduct was washed with four alternating cycles of methanol containing1% triethylamine and methylene chloride containing 1% triethylamine, anddried overnight in vacuo, to provide a resin bound compound of formula(7).

EXAMPLE 8 Preparation of a Compound of Formula I

[0240] A. Preparation of a Compound of Formula I in which R is Hydrogen,R¹ is Cyclopentyl, R² is Hydrogen, R³ is 2-Fluorophenyl, and X and Y areCovalent Bonds

[0241] The resin bound compound of formula (7) was suspended in asolution of 2% trifluoroacetic acid/5% methanol/methylene chloride andshaken (200 rpm) at room temperature for 2 hours. After removal of thesolution, the residue was rinsed with methylene chloride (3×0.5 mL), andthe combined filtrates were concentrated under reduced pressure toafford(4S,5S,3R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol,a compound of Formula I.

EXAMPLE 9

[0242] Hard gelatin capsules containing the following ingredients areprepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[0243] The above ingredients are mixed and filled into hard gelatincapsules.

EXAMPLE 10

[0244] A tablet formula is prepared using the ingredients below:Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0245] The components are blended and compressed to form tablets.

EXAMPLE 11

[0246] A dry powder inhaler formulation is prepared containing thefollowing components:

[0247] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

EXAMPLE 12

[0248] Tablets, each containing 30 mg of active ingredient, are preparedas follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

[0249] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 13

[0250] Suppositories, each containing 25 mg of active ingredient aremade as follows: Ingredient Amount Active Ingredient 25 mg Saturatedfatty acid glycerides to 2,000 mg

[0251] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 14

[0252] Suspensions, each containing 50 mg of active ingredient per 5.0mL dose are made as follows: Ingredient Amount Active Ingredient 50.0 mgXanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mgMicrocrystalline cellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mgFlavor and Color q.v. Purified water to 5.0 mL

[0253] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

EXAMPLE 15

[0254] A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 16

[0255] An injectable preparation is prepared having the followingcomposition: Ingredients Amount Active ingredient 2.0 mg/ml Mannitol,USP 50 mg/ml Gluconic acid, USP q.s. (pH 5-6) water (distilled, sterile)q.s. to 1.0 ml Nitrogen Gas, NF q.s.

EXAMPLE 17

[0256] A topical preparation is prepared having the followingcomposition: Ingredients grams Active ingredient 0.2-10 Span 60 2.0Tween 60 2.0 Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

[0257] All of the above ingredients, except water, are combined andheated to 60° C. with stirring. A sufficient quantity of water at 60° C.is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. 100 g.

EXAMPLE 18 Sustained Release Composition

[0258] Weight Preferred Ingredient Range (%) Range (%) Most PreferredActive ingredient 50-95 70-90 75 Microcrystalline cellulose (filler) 1-35  5-15 10.6 Methacrylic acid copolymer  1-35   5-12.5 10.0 Sodiumhydroxide 0.1-1.0 0.2-0.6 0.4 Hydroxypropyl methylcellulose 0.5-5.0 1-32.0 Magnesium stearate 0.5-5.0 1-3 2.0

[0259] The sustained release formulations of this invention are preparedas follows: compound and pH-dependent binder and any optional excipientsare intimately mixed(dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

[0260] The resulting tablets may be coated with an optional film-formingagent, for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropyl.methylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/ methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

[0261] The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

[0262] In order to influence the dissolution rate, the time during whichthe compound containing powder is wet mixed is controlled. Preferablythe total powder mix time, i.e. the time during which the powder isexposed to sodium hydroxide solution, will range from 1 to 10 minutesand preferably from 2 to 5 minutes. Following granulation, the particlesare removed from the granulator and placed in a fluid bed dryer fordrying at about 60° C.

EXAMPLE 19 Binding Assays—DDT, Cells Cell Culture

[0263] DDT cells (hamster vas deferens smooth muscle cell line) weregrown as monolayers in petri dishes using Dulbecco's Modified Eagle'sMedium (DMEM) containing 2.5 μg ml⁻¹ amphotericin B, 100 U ml⁻¹penicillin G, 0.1 mg ml⁻¹ streptomycin sulfate and 5% fetal bovine serumin a humidified atmosphere of 95% air and 5% CO₂. Cells were subculturedtwice weekly by dispersion in Hank's Balanced Salt Solution (HBSS)without the divalent cations and containing 1 mM EDTA. The cells werethen seeded in growth medium at a density of 1.2×10⁵ cells per plate andexperiments were performed 4 days later at approximately one daypreconfluence.

Membrane Preparations

[0264] Attached cells were washed twice with HBSS (2×10 ml), scrapedfree of the plate with the aid of a rubber policeman in 5 ml of 50 mMTris-HCl buffer pH 7.4 at 4° C. and the suspension homogenized for 10 s.The suspension was then centrifuged at 27,000×g for 10 min. The pelletwas resuspended in homogenization buffer by vortexing and centrifuged asdescribed above. The final pellet was resuspended in 1 vol of 50 mMTris-HCl buffer pH 7.4 containing 5 mM MgCl₂ for A₁ AdoR assays. For the[³⁵S]GTPγS binding assay the final pellet was resuspended in 50 mMTris-HCl pH 7.4 containing 5 mM MgCl₂, 100 mM NaCl and 1 mMdithiothreitol. This membrane suspension was then placed in liquidnitrogen for 10 min, thawed and used for assays. The protein content wasdetermined with a Bradford™ Assay Kit using bovine serum albumin asstandard.

Competitive Binding Assay

[0265] Pig striatum were prepared by homogenation in 50 mM Tris buffer(5×volume of tissue mass pH=7.4). After centrifugation at 19,000 rpm for25 minutes at 4° C., the supernatant was discarded, and the process wasrepeated twice. Compounds of Formula I were assayed to determine theiraffinity for the A₁ receptor in a pig striatum membrane prep or a DDT₁membrane prep. Briefly, 0.2 mg of pig striatal membranes or DDT₁ cellmembranes were treated with adenosine deaminase and 50 mM Tris buffer(pH=7.4) followed by mixing. To the pig membranes was added 2 μL ofserially diluted DMSO stock solution of the compounds of this inventionat concentrations ranging from 100 microM to 10 nM. The control received2 microL of DMSO alone, then the antagonist [³H] 8-cyclopentylxanthine(CPX) for pig striatum or the agonist [³H]2-chloro-6-cyclopentyladenosine (CCPA) for DDT₁ membranes in Tris buffer(50 mM, pH of 7.4) was added to achieve a final concentration of 2 nM.After incubation at 23° C. for 2 h, then the solutions were filteredusing a membrane harvester using multiple washing of the membranes (3×).The filter disks were counted in scintillation cocktail affording theamount of displacement of tritiated CPX or by the competitive binding ofcompounds of Formula I.

[0266] The compounds of Formula I were shown to be of high, medium, orlow affinity for the A₁ adenosine receptor in this assay.

EXAMPLE 20 [³⁵S]GTPγS Binding Assays

[0267] A₁-agonist stimulated [³⁵S] GTPγS binding was determined by amodification of the method described by Giersckik et al. (1991) andLorenzen et al. (1993). Membrane protein (30-50 μg) was incubated in avolume of 0.1 ml containing 50 mM Tris-HCl buffer pH 7.4, 5 mM MgCl₂,100 mM NaCl, 1 mM dithiothreitol, 0.2 units ml⁻¹ adenosine deaminase,0.5% BSA, 1 mM EDTA, 10 mM GDP, 0.3 nM [³⁵S]GTPγS and with or withoutvarying concentrations of CPA for 90 min at 30° C. Nonspecific bindingwas determined by the addition of 10 μM GTPγS. Agonist stimulatedbinding was determined as the difference between total binding in thepresence of CPA and basal binding determined in the absence of CPA.Previous reports have shown that agonist stimulated [³⁵S]GTPγS bindingwas dependent on the presence of GDP (Gierschik et al., 1991; Lorenzenet al., 1993; Traynor & Nahorski, 1995). In preliminary experiments, itwas found that 10 μM GDP gave the optimal stimulation of CPA dependent[³⁵S]GTPγS binding and this concentration was therefore used in allstudies. In saturation experiments, 0.5 nM [³⁵S]GTPγS was incubated with0.5-1000 nM GTPγS. At the end of the incubation, each suspension wasfiltered and the retained radioactivity determined as described above.

[0268] The compounds of Formula I were shown to be partial or fullagonists of the A1 adenosine receptor in this assay.

EXAMPLE 21 cAMP Assay

[0269] A scintillation proximity assay (SPA) using rabbit antibodiesdirected at cAMP using an added tracer of adenosine 3′,5′-cyclicphosphoric acid 2′-O-succinyl-3-[¹²⁵I]iodotyrosine methyl ester andfluoromicrospheres containing anti-rabbit specific antibodies asdescribed by Amersham Pharmacia Biotech (Biotrak cellular communicationassays). Briefly, DDT₁, cells were cultured in clear bottomed 96 wellmicrotiter plates with opaque wells at concentrations between 10⁴ to 10⁶cells per well in 40 μl of HBSS at 37° C. (5% CO₂ and 95% humidity). Thepartial or full A₁ agonists (5 μl)of this invention were incubated atvarious concentrations with the DDT₁, cells in the presence of rolipram(50 μM), and 5 μM forskolin for 10 min at 37° C. The cells wereimmediately lysed by treatment 5 μl of 10% dodecyltrimethylammoniumbromide followed by shaking using microplate shaker. After incubation ofthe plate for 5 minutes, an immunoreagent solution (150 μl containingequal volumes of tracer, antiserum, and SPA fluorospheres) was added toeach well followed by sealing the plate. After 15-20 h at 23° C., theamount of bound [¹²⁵I] cAMP to the fluoromicrospheres was determined bycounting in a microtitre plate scintillation counter for 2 minutes.Comparison of counts with standard curves generated for cAMP using asimilar protocol afforded the cAMP present after cell lysis.

[0270] The compounds of Formula I were shown to be functionally activeas A₁ agonists with a partial or full decrease in cAMP in this assay.

[0271] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. All patents and publications cited above arehereby incorporated by reference.

What is claimed is:
 1. A compound of the formula:

wherein: R is hydrogen or lower alkyl; R¹ is optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted aryl,or optionally substituted heteroaryl; or R and YR¹ when taken togetherwith the nitrogen atom to which they are attached represents optionallysubstituted heterocyclyl; R² is hydrogen, halo, trifluoromethyl, acyl,or cyano; R³ is optionally substituted cycloalkyl, optionallysubstituted aryl; optionally substituted heteroaryl, or optionallysubstituted heterocyclyl, R⁴ and R⁵ are independently hydrogen or acyl;and X and Y are independently a covalent bond or optionally substitutedalkylene; with the proviso that when R¹ is methyl and Y is a covalentbond, R³ cannot be phenyl when X is methylene or ethylene.
 2. Thecompound of claim 1, wherein R³ is optionally substituted aryl oroptionally substituted heteroaryl.
 3. The compound of claim 2, whereinR, R², R⁴ and R⁵ are all hydrogen.
 4. The compound of claim 3, whereinR³ is optionally substituted aryl.
 5. The compound of claim 4, whereinR¹ is optionally substituted cycloalkyl, X is a covalent bond, and R³ isoptionally substituted phenyl.
 6. The compound of claim 5, wherein Y isa covalent bond, R¹ is optionally substituted cyclopentyl and R³ isphenyl substituted by halogen.
 7. The compound of claim 6, wherein R¹ is2-hydroxycyclopentyl and R³ is 2-fluorophenyl, namely(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]-2-{6-[(2-hydroxycyclopentyl)amino]-purin-9-yl}oxolane-3,4-diol.8. The compound of claim 4, wherein Y is optionally substituted loweralkylene, R¹ and R³ are both optionally substituted phenyl, and X is acovalent bond.
 9. The compound of claim 8, wherein Y is —CH₂CH₂—, R¹ isphenyl, and R³ is 2-methylphenyl.
 10. The compound of claim 8, wherein Yis —CH₂CH₂—, and R¹ and R³ are both phenyl.
 11. The compound of claim 8,wherein Y is 3-phenylpropylene, R¹ is phenyl, and R³ is2,4-fluorophenyl.
 12. The compound of claim 4, wherein X and Y are bothcovalent bonds, R¹ is optionally substituted alkyl or optionallysubstituted phenyl, and R³ is optionally substituted phenyl.
 13. Thecompound of claim 12, wherein R¹ is 2-fluorophenyl, and R³ is phenyl.14. The compound of claim 12, wherein R¹ is pent-3-yl, and R³ is2-fluorophenyl.
 15. The compound of claim 12, wherein R¹ is2-ethylhexyl, and R³ is 2-fluorophenyl.
 16. The compound of claim 12,wherein R¹ is 2-methylbutyl, and R³ is phenyl.
 17. The compound of claim3, wherein R³ is optionally substituted heteroaryl.
 18. The compound ofclaim 17, wherein X and Y are both covalent bonds, R¹ is optionallysubstituted cycloalkyl, and R³ is optionally substituted1,3-thiazol-2-yl.
 19. The compound of claim 18, wherein R¹ isbicyclo[2.2.1]hept-2-yl and R³ is 4-methyl-1,3-thiazol-2-yl.
 20. Thecompound of claim 17, wherein Y is lower alkylene, R¹ is optionallysubstituted cycloalkyl or optionally substituted phenyl, and R³ isoptionally substituted 1,3-thiazol-2-yl.
 21. The compound of claim 20,wherein Y is ethylene, R¹ is 3-chlorophenyl, and R³ is4-methyl-1,3-thiazol-2-yl.
 22. The compound of claim 20, wherein Y isbutylen-2-yl, R¹ is phenyl, and R³ is 4-methyl-1,3-thiazol-2-yl.
 22. Thecompound of claim 20, wherein Y is methylene, R¹ is cyclopropyl, and R³is 2-methyl-1,3-thiazol-2-yl.
 23. The compound of claim 17, wherein Y ismethylene, R¹ is cyclopropyl, and R³ is 1,3-benzoxazol-2-yl.
 24. Thecompound of claim 2, wherein R², R⁴ and R⁵ are all hydrogen and R andYR¹ when taken together with the nitrogen atom to which they areattached represents optionally substituted heterocyclyl.
 25. Thecompound of claim 24, wherein R³ is optionally substituted phenyl oroptionally substituted heteroaryl and X is a covalent bond.
 26. Thecompound of claim 25, wherein the optionally substituted heterocyclyl ispyrrolidin-1-yl and R³ is 4-methyl-1,3-thiazol-2-yl.
 27. A method oftreating a disease state in a mammal that is alleviable by treatmentwith a partial or full A₁ adenosine receptor agonist, comprisingadministering to a mammal in need thereof a therapeutically effectivedose of a compound of Formula I.
 28. The method of claim 27, wherein thedisease state is chosen from atrial fibrillation, supraventriculartachycardia and atrial flutter, congestive heart failure, epilepsy,stroke, diabetes, obesity, ischemia, stable angina, unstable angina,cardiac transplant, and myocardial infarction.
 29. A pharmaceuticalcomposition comprising at least one pharmaceutically acceptableexcipient and a therapeutically effective amount of a compound ofFormula I.